JPH0120149B2 - - Google Patents

Abstract

2-Oxo-hexahydroazepine, -piperidine or pyrrolidines of formula <IMAGE> wherein n is 2,3 or 4, R is hydrogen, lower alkyl, aryl(lower)alkyl, loweralkenylmethyl or cycloalkylmethyl, R1 is hydrogen or lower alkyl and R2 is hydrogen, lower alkyl or aryl(lower)alkyl are prepared by a novel process involving reaction of an anion of a lactam of formula <IMAGE> where R3 is lower alkyl, aryl(lower)alkyl, trialkyl-, triaryl- or triarylalkyl-silyl with a benzyne of formula <IMAGE> where R4 is lower alkyl, aryl(lower)alkyl or trialkyl-, triaryl- or triarylalkyl-silyl. The products are useful as intermediates for preparing pharmacologically active 2-unsubstituted -hexahydroazepine, -piperidine and pyrrolidine derivatives.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to hexahydroazepine, piperidine and pyrrolidine derivatives. More particularly, the present invention relates to 2-oxo-hexahydroazepine, -piperidine and -pyrrolidine derivatives.

The 2-oxo-hexahydroazepine, -piperidine and pyrrolidine derivatives produced by the novel method of the present invention have the general formula () , where n is 2, 3 or 4, and R is hydrogen, lower alkyl, aryl (lower) alkyl,
lower alkenylmethyl or cycloalkylmethyl, R ¹ is hydrogen or lower alkyl, R ²
is hydrogen, lower alkyl or aryl(lower) alkyl.

These derivatives are expressed by the general formula () (wherein n, R and R ² are as defined above and R ⁵ is lower alkyl) Good too. General formula where R ¹ is hydrogen ()
C-alkylation (e.g. by reaction with an alkyl halide in the presence of a strong base) of a compound of the general formula () in which R ¹ is lower alkyl
It may be converted into a compound. Compounds of general formula ( ) in which R ¹ is lower alkyl may be reduced (eg, with a hydride transfer agent such as lithium aluminum hydride) to provide compounds of general formula. Compounds of general formula ( ) in which R ² is lower alkyl or aryl(lower) alkyl may be subjected to ether cleavage (eg with hydrogen bromide or boron tribromide) to provide compounds in which R ² is hydrogen. The use of compounds of formula () and their preparation from compounds of formula () are further illustrated, for example, in UK Patent Specification No. 1285025 and European Patent Application Publication No. 0003253. The present invention provides a new method for producing intermediates of general formula ().

According to the present invention, the general formula () (In the formula, n and R ¹ are the same as defined above,
R ³ is lower alkyl, aryl (lower) alkyl,
trialkyl-, triaryl- or triarylalkyl-silyl, lower alkenylmethyl or cycloalkylmethyl), the anion of a lactam derivative of general formula () (wherein R ⁴ is lower alkyl, aryl(lower) alkyl or trialkyl-, triaryl- or triarylalkyl-silyl), the anion of the compound of general formula where R ¹ is lower alkyl or to obtain a dianion of a compound of the general formula in which R ¹ is hydrogen (if desired, the dianion in which R ¹ is hydrogen is reacted with a (lower) alkylating agent to obtain an anion of a compound of the general formula in which R ¹ is lower alkyl) ),
The present invention also provides a method for producing a compound represented by the general formula (), which comprises protonating an anion or dianion of the compound represented by the general formula to obtain a compound represented by the general formula.

The term "lower" as used herein means that the referenced group contains from 1 to 6 carbon atoms. The group preferably contains 1 to 4 carbon atoms. For example, R or
When R ² is lower alkyl, this group may be, for example, methyl, ethyl, propyl or butyl. Similarly R ¹ may be, for example, methyl, ethyl, propyl or butyl. R,
When R ² , R ³ or R ⁴ is aryl(lower)alkyl, this group is preferably a phenyl(lower)alkyl group, such as phenethyl or benzyl, and the phenyl group is, for example, substituted with a substituent such as alkyl or alkoxy. Therefore, it may be replaced. When R or R ³ is lower alkenylmethyl, the group is preferably allyl. R or
When R ³ is cycloalkylmethyl, the group is preferably cyclopropylmethyl or cyclobutylmethyl.

The anion of a lactam with the general formula (
potassium or lithium, and A is a secondary amine group). The compound MA is a metal amide and is itself a metal compound MR ⁵ (where M is sodium, potassium or lithium and R ⁵
is alkyl, aryl or aralkyl)
is preferably produced in that case by reacting with a secondary amine. Secondary amines are dialkylamines such as diethylamine, di-isopropylamine, di-tert-butylamine, di-cyclohexylamine, t -butyl-cyclohexylamine, Nt -amyl- Nt -butylamine, N-isopropyl-N -cyclohexylamine or N-(1'-ethylcyclohexyl)-
1,1',3,3-tetramethylbutylamine or cyclic compounds such as piperidine or 2,
It may also be 2,6,6-tetramethylpiperidine. Preferably, the lactam anion is the lactam anion, which is prepared in situ from lithium 2,2,6,6-tetramethylpiperidide (the compound is prepared in situ from 2,2,6,6-tetramethylpiperidine and, for example, butyllithium). It is preferable that it be produced by reacting with

Benzyne with the general formula (), for example, has the general formula () [In the formula, R ⁴ is as defined above and Hal is chlorine, bromine or iodine (preferably chlorine)]
It is produced in situ by the reaction of a substituted halobenzene with a strong base, such as the agent mentioned above for the anion production of a lactam of formula (). Preferably the strong base is lithium 2,2,6,6-tetramethylpiperidide (which may be generated in situ as described above).

In a particularly preferred method, the anion production of lactam () and the production of benzyne are performed in the same reaction vessel to obtain the anion or dianion of compound (). For example, bases such as lithium 2,2,
6,6-tetramethylpiperidide (generated in situ) may be reacted with a lactam of formula ( The compound may be generated in situ (for example by adding an alkyllithium such as butyllithium) and then the substituted halobenzene ( ) may be added. It is preferable to add the substituted halobenzene (2) to the required amount in two or more portions together with the production of lithium 2,2,6,6-tetramethylpiperidide or other base.

The anion or dianion of compound () may be protonated without being isolated. For example, it may be protonated by reaction with water or a dilute aqueous mineral acid (e.g. dilute hydrochloric acid), e.g. excess water may be added to the reaction vessel, or the reaction mixture may be added to the water. . If desired, the dianion of a compound in which R ¹ is hydrogen is reacted with a (lower) alkylating agent, such as a lower alkyl halide (preferably lower alkyl iodide), to form R ¹
An anion of formula () may also be obtained, where is lower alkyl. This anion may then be protonated, for example, by reaction with water.

When R ³ and/or R ⁴ are trialkyl-, triaryl- or triarylalkyl-silyl, hydrolysis of the product gives compounds of formula where R and/or R ² are hydrogen.
Hydrolysis may be carried out by reaction with water during protonation of the anion or dianion of the compound ().

^The lactams of the general formula
can be produced by "alkylation".

Example 1 3-ethylhexahydro-3-(3-methoxyphenyl)-1-methyl-2H-azepine-2-
A solution of butyllithium (0.05 mol) in hexane (31.25 ml) was dissolved with 2,2,6,6-tetramethylpiperidine (8.5 ml) and then with dry tetrahydrofuran ("THR"; 100 ml) under an inert atmosphere. Process at 0°C. This mixture was combined with N-methylcaprolactam (6.25ml, 50mM) in THF (20ml).
solution and stir for 30 minutes. A solution of butyllithium (0.05 mol) in hexane (31.25 mM) is added and the mixture is stirred for 15 minutes.
O-chloranisole (6.2ml) in THF (20ml)
is added slowly, the mixture is stirred for 1.5 hours and treated with ethyl iodide (5.15 ml). After 1 hour, the reaction was quenched with water (100 ml),
The solvent is removed under reduced pressure. The residue was dissolved in 2NHCl (200
ml) and toluene (250 ml). The organic layer was washed with brine, dried and the solvent removed under reduced pressure to give 3-ethylhexahydro-3-(3
-methoxyphenyl)-1-methyl- 2H -azepin-2-one (5.5 g), boiling point 140°/0.1 mm, is obtained. Recrystallization from diisopropyl ether gives the purified title compound (5.0 g), melting point: 68-69°C (same as the standard).

Example 2 Hexahydro-3-(3-methoxyphenyl)-
1-Methyl-2H-azepin-2-one Butyllithium (0.05 ml) in hexane (34.4 ml)
A solution of mol) in 2,2,6,6-tetramethylpiperidine (9.3 ml) and then in dry THF (100 ml)
at 0° C. under an inert atmosphere. This mixture was added to N-methylcaprolactam (6.9ml, 55mM).
and stir for 30 minutes. Hexane (34.4
A solution of butyllithium (0.05 mol) in ml) is added and the reaction mixture is stirred for 15 minutes and then treated with O-chloroanisole (3.1 ml). After 30 minutes a solution of butyllithium (0.05 mol) in hexane (31.25 ml) is added and the mixture is stirred for 15 minutes and treated with O-chloroanisole (3.1 ml).
After another 30 minutes, the reaction was quenched with water (100 ml) and
and the solvent is removed under reduced pressure. 5NHCl the residue
(100ml) and toluene (250ml). The organic layer is washed with brine, dried and the solvent is removed under reduced pressure.

Distillation of the residue gives the crude title compound (5.4 g), boiling point 150°/0.5 mm. Purified material (4.2 g) recrystallized from diisopropyl ether, mp 74
Obtain ~75 °C (same as standard).

Example 3 Hexahydro-3-(3-methoxyphenyl)-
1-Methyl-2H-azepin-2-one Butyllithium (0.05 ml) in hexane (31.25 ml)
A solution of mol) is treated with 2,2,6,6-tetramethylpiperidine (8.5 ml) and then with THF (100 ml) under an inert atmosphere at 0°C. N-Methylcaprolactam (6.25ml, 50mM) in THF (20ml)
The mixture is stirred for 30 minutes and treated with a solution of butyllithium (0.05 mol) in hexane (31.25 ml). After 15 minutes, O-
Add chloranisole (6.2ml) and stir the mixture.
Stir at ambient temperature for 15 hours.

The reaction is quenched with water (100ml), the solvent is removed under reduced pressure and the residue is partitioned between 5NHCl (100ml) and toluene (250ml). The organic layer is washed with brine, dried and the solvent is removed under reduced pressure. Distillation of the residue yields the crude title compound (40%), boiling point approximately 140°/0.05 mm. Purified material (31%) recrystallized from isopropyl ether, mp 74-75°C
(same as the standard material).

Example 4 3-ethylhexahydro-3-(3-methoxyphenyl)-1-methyl-2H-azepine-2-
2,2,6,6-tetramethylpiperidine (8.48 g) was cooled under nitrogen and mixed with hexane (31.25 ml) and tetrahydrofuran (15 g) with stirring.
Add dropwise to a solution of butyllithium (0.05 mol) in ml). 3-Ethyl-hexahydro-1-methyl-2H in dry tetrahydrofuran (20ml)
-Add azepin-2-one (7.75g). Once this addition is complete, a further portion of butyllithium (0.06 mol) in hexane (37.5 ml) is added with cooling. After 10 minutes O-chloranisole (8.54
g) dropwise into tetrahydrofuran (20 ml). The reaction is then stirred for approximately 20 hours at ambient temperature. The reaction mixture is poured into water and the tetrahydrofuran is removed under reduced pressure. After acidifying with 5M hydrochloric acid, the mixture is extracted with toluene. The toluene extract was washed with water, dried (MgSO ₄ ), and after removing the solvent, the product was distilled to yield 2.37 g, boiling point 0.6 mm.
A temperature of 150 to 170℃ is obtained. The yield of the title compound is 15.8% when corrected for purification by GLC analysis.

Example 5 Hexahydro-3-(3-methoxyphenyl)-
2H-azepin-2-one Hexahydro-1-trimethylsilyl-2H-azepine- in dry tetrahydrofuran (20 ml)
While cooling 2-one (9.2 g) under nitrogen atmosphere and stirring, lithium-2,2,6,6-tetramethylpiperidide [2,2,6,6-tetramethylpiperidine (8.48 g)] was added. and butyllithium (0.06 mol) in hexane-tetrahydrofuran (38 ml; 10 ml)].
A further portion of butyllithium (0.06 mol) in hexane (38 ml) is then added followed by O-chloroanisole (8.54 g) keeping the reaction temperature between -10° and 5°C. After warming to room temperature,
The reaction is stirred for 1.5 hours and then decomposed by the addition of water (100ml). The solvent is removed under reduced pressure and the resulting product is partitioned between toluene and 5M hydrochloric acid. The toluene extract was dried (MgSO ₄ ), the solvent was removed and the product was distilled to 2.7 g, boiling point 0.1 mm ~ 160
Obtain 170℃. The yield of crystallized title compound from ethyl acetate is 2.6 g.

Example 6 1-Benzylhexahydro-3-(3-methoxyphenyl)2H-azepin-2-one 1-Benzylhexahydro- 2H- azepin-2-one (10.2 g) in tetrahydrofuran (100 ml) was Lithium-2,2,6,6-tetramethylpiperidide [prepared by adding 2,2,6,6-tetramethylpiperidine (8.5 g) to butyllithium (0.05 mol) in hexane (32 ml). [prepared under nitrogen] and added dropwise to the stirred, cooled solution. Cool this solution to 0°C,
and O-chloranisole (6.2 ml) is added dropwise. After stirring for 4 hours at room temperature, the reaction was decomposed with water and
The solvent is removed under reduced pressure. 5M of the obtained oil
Partition between hydrochloric acid and toluene. Drying ( _MgSO4 )
After removing the toluene, an oil was obtained which was distilled to obtain 5.02 g, boiling point 180-220°C/0.2 mm. 3.15 g of oil recrystallized from methanol, melting point
Obtain 120-122℃.

analysis: Actual value C; 77.6; H 7.7; N 4.6%.

C ₂₀ H ₂₃ NO ₂ Calculated value C 77.6; H 7.5; N 4.5% Example 7 Hexahydro-3-(3-methoxyphenyl)-
1-Methyl-2H-azepin-2-one Diisopropylamine (152 g) in tetrahydrofuran (150 ml) was added to 15% butyllithium in hexane (641 g, 1.50 mol) under nitrogen at 20-25°C over 30 minutes. and the mixture is stirred for 30 minutes at room temperature. N-Methylcaprolactam (63.6 ml) in tetrahydrofuran (60 ml)
g) was added over 5 minutes with cooling below 25°C, the mixture was stirred for 1 hour at room temperature and then O-
Chloranisole (71.3 g) is added over 20 minutes keeping the temperature below 30°C. The reaction mixture was stirred for 2 hours, water (1) was added, the product was extracted into ethyl acetate (2 x 1), the extracts were combined and washed with 2N hydrochloric acid (1) and water (500 ml). death,
and evaporation under reduced pressure to obtain 27.1 g of oil.

The crude product was purified by column chromatography.
Purification by eluting with toluene on a basic alumina column and concentrating the fractions gives 8.7 g of the title compound, melting point 74-76°C.

Example 8 3-(3rhydroxyfer)-1-methyl-2-
Pyrrolidone Following the steps of Example 3, the lithium anion of 1-methyl-2-piperidine is reacted with m-benzylbenzyne (from lithium 2,2,6,6-tetramethylpiperidide and O-benzyloxychlorobenzene). 3 by subsequent mixing with an aqueous substance.
-(3-methoxyphenyl)-1-methyl-2-pyrrolidone is obtained.

The protecting group was removed using iodotrimethylsilane to give the title mixture, mp 113-4°C (ethyl acetate-
hexane), is obtained.

Example 9 3-(3-hydroxyphenyl)-1-methyl-
2-Piperidone Following the steps in Example 3, the lithium anion of 1-methyl-2-piperidine was converted from m-benzyloxybenzyne (lithium 2,2,6,6-tetramethylpiperidide and O-benzyloxychlorobenzene). ) and then admixture with aqueous to give 3-(3-benzyloxyphenyl)-1-methyl-2-piperidone. The title compound, 1/
The tetrahydrate, melting point 111-4°C (hexane), is obtained.

Example 10 Hexahydro-3-(3-hydroxyphenyl)
-1-Methyl-2H-azepin-2-one Following the steps of Example 3, the lithium anion of N-methylcaprolactam was added to m-triphenylsilyloxybenzyne (O-chlorotriphenylsilyloxybenzene and lithium tetramethylpiperidide). (from ethyl acetate) followed by admixture with aqueous acid to give the title compound, mp 192-3°C (ethyl acetate).

Claims (1)

[Claims] 1 General formula () (wherein n is 2, 3 or 4, R is hydrogen, lower alkyl, aryl (lower) alkyl, lower alkenylmethyl or cycloalkylmethyl,
R ¹ is hydrogen or lower alkyl and R ² is hydrogen, lower alkyl or aryl (lower) alkyl). , general expression () (In the formula, n and R ¹ are the same as defined above,
R ³ is lower alkyl, aryl (lower) alkyl,
trialkyl-, triaryl- or triarylalkyl-silyl, lower alkenylmethyl or cycloalkylmethyl), the anion of a lactam derivative of general formula () (wherein R ⁴ is lower alkyl, aryl(lower) alkyl or trialkyl-, triaryl- or triarylalkyl-silyl), the anion of the compound of general formula where R ¹ is lower alkyl Or a method for producing the same, which comprises producing a dianion of a compound of the general formula in which R ¹ is hydrogen, and protonating the anion or dianion of the compound of the general formula to obtain a compound of the general formula. 2 General formula () (wherein n is 2, 3 or 4, R is hydrogen, lower alkyl, aryl (lower) alkyl, lower alkenylmethyl or cycloalkylmethyl,
R ¹ is lower alkyl and R ² is hydrogen, lower alkyl or aryl (lower) alkyl). formula() (where n is as defined above, R ¹ is hydrogen, and R ³ is lower alkyl, aryl(lower) alkyl, trialkyl-, triaryl- or triarylalkyl-silyl, lower alkenylmethyl or cycloalkylmethyl.The anion of a lactam derivative with the general formula () (wherein R ₄ is lower alkyl, aryl (lower) alkyl, or trialkyl-, triaryl- or triarylalkyl-silyl) to form a dianion of a compound of the general formula in which R ¹ is hydrogen. the dianion is reacted with a (lower) alkylating agent to form an anion of a compound of general formula in which R ¹ is lower alkyl, and the dianion of a compound of general formula is protonated to form a compound of general formula. Its manufacturing method consists of obtaining.